Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are two common disorders of gut–brain interaction. Affected patients often first present to their primary care providers seeking care for symptoms of constipation, abdominal pain, and bloating, which have a significant impact on their health-related quality of life. These patients often require extensive counseling and reassurance, and knowledge of reliable diagnostic criteria and treatment options is imperative to managing their conditions. Family medicine practitioners, including nurse practitioners and physician assistants, are uniquely qualified to provide a diagnosis and safe, effective management of these disorders. This article reviews the latest evidence and provides practical advice related to diagnosis and management of IBS-C and CIC.
Background Linaclotide (LIN) is a guanylate cyclase-C agonist approved to treat adults with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). As LIN is a 14-amino acid peptide, no absorption from the gastrointestinal tract is expected following oral administration. However, LIN levels in human breast milk have not been determined. Aims To determine the levels of LIN and its active metabolite, MM-419447, excreted in breast milk after multiple once-daily doses of LIN (72 µg, 145 μg, or 290 μg) in lactating women. Methods This was a multicenter, open-label, multidose, Phase 1, milk-only lactation study (NCT02220348) in lactating women aged 18–45 years who were actively breastfeeding or pumping for ≥4 weeks and were already taking LIN 72 μg, 145 μg, or 290 μg therapeutically for IBS-C or CIC. Participants continued their LIN dose once daily for the 3 study days, with breast milk extractions at −1 to 0 hours (pre-dose) on Day 1 and −1 to 0 hours and 0–2, 2–4, 4–8, 8–12, 12–16, and 16–24 hours after dosing on Day 3. The pharmacokinetic endpoints were the cumulative amount of LIN and MM-419447 and the percentage dose of LIN excreted into the breast milk over the dosing interval. Adverse events (AEs) were monitored. The study has institutional review board approval. Results Seven women were enrolled in the study (IBS-C, n=1; CIC, n=6) and received LIN (72 μg, n=5; 145 μg, n=1; and 290 μg, n=1). Mean age was 28 (range: 19–35), mean weight was 70 kg (standard deviation [SD]: 12 kg), and mean body mass index was 26 kg/m2 (SD: 4 kg/m2); the majority were white (n=6). Concentrations of LIN and MM-419447 in breast milk samples were below the quantitation limits (<0.25 ng/mL and <1.00 ng/mL, respectively) at all time points for all participants. Cumulative exposure for each dose was 216 μg (72 μg dose), 435 μg (145 μg dose), and 870 μg (290 μg dose). One treatment-emergent AE was reported (mild rash). Conclusions The data collected in this study provide no evidence that breastfeeding infants receive LIN or MM-419447 through breast milk as their concentrations were below the quantitation limit following multiple once-daily doses of LIN 72 μg, 145 μg, or 290 μg. Funding Agencies This study was sponsored by Allergan plc, Dublin, Ireland (prior to acquisition by AbbVie Inc.). Writing and editorial assistance were provided to the authors by Stephanie J. Rippon, MBio, Jane Beck, MA, and Rebecca Fletcher, BA(Hons), of Complete HealthVizion, Inc., Chicago, IL, USA and funded by Allergan plc (prior to acquisition by AbbVie Inc.).
Background Linaclotide (LIN) is a guanylate cyclase-C agonist approved to treat irritable bowel syndrome with constipation (IBS-C) in adults. Abdominal symptoms are important to patients with IBS-C. In a recent Phase 3b study, LIN significantly improved a composite score of abdominal bloating, pain, and discomfort (Abdominal Score), which was used as the primary endpoint in the study. Aims To evaluate the efficacy of LIN for improving additional efficacy abdominal symptom endpoints in a randomized, double-blind, placebo (PBO)-controlled Phase 3 study of LIN in patients with IBS-C. Methods Adults with IBS-C were randomized to PBO (N=308) or LIN 290 μg (N=306) once daily for 12 weeks. Patients recorded their daily abdominal symptoms, including the individual items of bloating, pain, and discomfort, using an 11-point scale (0–10; 0=none, 10=worst possible). The primary endpoint was the Abdominal Score. Additional efficacy endpoints included 6/12-week abdominal pain and constipation (APC)+1 responder, 6/12-week abdominal bloating responder, 6/12-week abdominal pain responder, and 6/12-week abdominal discomfort responder. For individual symptoms, a responder was a patient who had an improvement from baseline of ≥2 points in the respective endpoint for ≥6 of the 12 weeks. Changes from baseline (CFB) over 12 weeks in abdominal bloating, pain, and discomfort were evaluated using a mixed model with repeated measures framework. Proportions of responders were compared between groups for each responder endpoint using a Cochran-Mantel-Haenszel test. Results 614 patients (mean age, 46.7 years; 81% female; similar baseline abdominal symptoms) were randomized. LIN-treated patients had greater least-squares mean (LSM) CFB in abdominal bloating (LSM difference [95% CI]: –0.889 [–1.249, –0.530], p<0.001), pain (–0.881 [–1.238, –0.524], p<0.001), and discomfort (–0.837 [–1.196, –0.478], p<0.001) compared to PBO-treated patients. There was a greater proportion of LIN-treated vs. PBO-treated patients who were 6/12-week APC+1 (29% vs. 17%; p=0.0003), bloating (40% vs. 24%; p<0.001), pain (42% vs. 25%; p<0.001), and discomfort (42% vs. 26%; p<0.001) responders (Figure). Diarrhea was the most common treatment-emergent adverse event (LIN: 4.6%; PBO: 1.6%). Conclusions LIN significantly improved multiple abdominal symptom and secondary responder endpoints in patients with IBS-C. These results support the effectiveness of LIN for improving a spectrum of abdominal symptoms in IBS-C. Funding Agencies This study was sponsored by Allergan plc, Dublin, Ireland (prior to acquisition by AbbVie Inc.). Writing and editorial assistance were provided to the authors by Brittany Y. Jarrett, PhD, Jane Beck, MA, and Rebecca Fletcher, BA(Hons) of Complete HealthVizion, Inc., Chicago, IL, USA and funded by Allergan plc (prior to acquisition by AbbVie Inc.).
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